US8969342B2 - Compounds and methods for treating mammalian gastrointestinal microbial infections - Google Patents

Compounds and methods for treating mammalian gastrointestinal microbial infections Download PDF

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US8969342B2
US8969342B2 US13/257,418 US201013257418A US8969342B2 US 8969342 B2 US8969342 B2 US 8969342B2 US 201013257418 A US201013257418 A US 201013257418A US 8969342 B2 US8969342 B2 US 8969342B2
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impdh
aforementioned compounds
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US20120101096A1 (en
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Lizbeth K. Hedstrom
Gregory D. Cuny
Deviprasad R. Gollapalli
Boris Striepen
Suresh Kumar Gorla
Mandapati Kavitha
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Brigham and Womens Hospital Inc
Brandeis University
University of Georgia Research Foundation Inc UGARF
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Definitions

  • Organisms must synthesize nucleotides in order for their cells to divide and replicate. Nucleotide synthesis in mammals may be achieved through one of two pathways: the de novo synthesis pathway; or the salvage pathway. Different cell types use these pathways to differing extents.
  • Inosine-5′-monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the biosynthesis of guanine nucleotides.
  • IMPDH catalyzes the NAD-dependent oxidation of inosine-5′-monophosphate (IMP) to xanthosine-5′-monophosphate (XMP) [Jackson R. C. et. al., Nature, 256, pp. 331-333, (1975)]. Regardless of species, the reaction involves the random addition of substrates. A conserved active site Cys residue attacks the C2 position of IMP and hydride is transferred to NAD, producing NADH and the E-XMP* intermediate.
  • NADH is released and a mobile flap folds into the vacant NADH site, E-XMP* hydrolyzes and XMP is released [W. Wang and L. Hedstrom, Biochemistry 36, pp. 8479-8483 (1997); J. Digits and L. Hedstrom, Biochemistry 38, pp. 2295-2306 (1999); Gan et al, Biochemistry 42, pp 847-863 (2003)].
  • the hydrolysis step is at least partially rate-limiting in all of the IMPDHs examined to date.
  • the enzyme is unusual in that a large conformational change occurs in the middle of a catalytic cycle.
  • IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y. Natsumeda & S. F. Carr, Ann N.Y. Acad., 696, pp. 88-93 (1993)].
  • the prokaryotic forms share 30-40% sequence identity with the human enzyme.
  • Each is 514 amino acids, and they share 84% sequence identity.
  • Both IMPDH type I and type II form active tetramers in solution, with subunit molecular weights of 56 kDa [Y. Yamada et. al., Biochemistry, 27, pp. 2737-27
  • IMPDH guanine nucleotides
  • B- and T-lymphocytes These cells depend on the de novo, rather than salvage pathway to generate sufficient levels of nucleotides necessary to initiate a proliferative response to mitogen or antigen [A. C. Allison et. al., Lancet II, 1179, (1975) and A. C. Allison et. al., Ciba Found. Symp., 48, 207, (1977)].
  • IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
  • Immunosuppression has been achieved by inhibiting a variety of enzymes including, for example, the phosphatase calcineurin (inhibited by cyclosporin and FK-506); dihydroorotate dehydrogenase, an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar); the kinase FRAP (inhibited by rapamycin); and the heat shock protein hsp70 (inhibited by deoxyspergualin).
  • the phosphatase calcineurin inhibited by cyclosporin and FK-506
  • dihydroorotate dehydrogenase an enzyme involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar)
  • the kinase FRAP inhibited by rapamycin
  • the heat shock protein hsp70 inhibited by deoxyspergualin
  • Inhibitors of IMPDH are also known.
  • Immunosuppressants such as MPA are useful drugs in the treatment of transplant rejection and autoimmune diseases. [R. E. Morris, Kidney Intl., 49, Suppl. 53, S-26, (1996)]. However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity and poor bioavailability. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)].
  • a novel noncompetitive inhibitor of meriniepodib has immunosuppressive activity, is orally bioavailable, and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of ⁇ 100 nM.
  • merimepodib is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation. It is currently in clinical trials to treat hepatitis C virus.
  • Nucleoside analogs such as tiazofurin, ribavirin and mizoribine also inhibit IMPDH [L. Hedstrom, et. al. Biochemistry, 29, pp. 849-854 (1990); L. Hedstrom, et al. Curr. Med. Chem. 1999, 6, 545-561]. These compounds require activation to either the adenine dinucleotide (tiazofurin) or monophosphate derivatives (ribavirin and mizoribine) that inhibit IMPDH. These activation pathways are often absent in the cell of interest. In addition, nucleoside analogs suffer from lack of selectivity and can be further metabolized to produce inhibitors of other enzymes. Therefore, nucleoside analogs are prone to toxic side effects.
  • Mycophenolate mofetil a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute renal allograft rejection following kidney transplantation. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger, Transplantation, 60, pp. 225-232 (1995)]. Several clinical observations, however, limit the therapeutic potential of this drug. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995)]. MPA is rapidly metabolized to the inactive glucuronide in vivo. [A. C., Allison and E. M. Eugui, Immunological Reviews, 136, pp.
  • the glucuronide then undergoes enterohepatic recycling causing accumulation of MPA in the gastrointestinal tract where it cannot exert its IMPDH inhibitory activity on the immune system. This fact effectively lowers the drug's in vivo potency, while increasing its undesirable gastrointestinal side effects.
  • IMPDH also plays a role in other physiological events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumor cell lines, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy [M. Nagai et. al., Cancer Res., 51, pp. 3886-3890, (1991)]. IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH, such as MPA, may be useful in preventing restenosis or other hyperproliferative vascular diseases [C. R. Gregory et al., Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; and PCT publication WO 94/01105].
  • IMPDH has been shown to play a role in viral replication in some viral cell lines. [S. F. Carr, J. Biol. Chem., 268, pp. 27286-27290 (1993)]. Analogous to lymphocyte and tumor cell lines, the implication is that the de novo, rather than the salvage, pathway is critical in the process of viral replication.
  • Cryptosporidiosis is a severe gastrointestinal disease caused by protozoan parasites of the genus Cryptosporidium .
  • the most common causes of human disease are C. parvum and C. hominis , though disease can also result from C. felis, C. meleagridis, C. canis , and C. muris infection.
  • Small children, pregnant women, the elderly, and immuno-compromised people are at risk of severe, chronic and often fatal infection. [Carey, C. M., Lee, H., and Trevors, J. T., Water Res., 38, 818-62 (2004); and Fayer, R., Veterinary Parasitology, 126, 37-56 (2004)].
  • the Cryptosporidium parasites produce spore-like oocysts that are highly resistant to water chlorination.
  • Several large outbreaks in the U.S. have been linked to drinking and recreational water. Infection rates are extremely high, with disease manifest in 30% of exposed individuals and a 50-70% mortality rate among immuno-compromised individuals.
  • IMPDH is a key enzyme in the purine salvage pathway of C. parvum .
  • IMPDH is a validated drug target in immunosuppressive, cancer and viral therapy, so the human enzymes are extremely well studied. It has recently been shown that C. parvum IMPDH has very different properties than the human enzymes and that IMPDH inhibitors block parasite proliferation in vivo [N. N. Umejiego et al, J Biol Chem, 279 pp. 40320-40327 (2004); and B. Striepen et al, Proc Natl Acad Sci USA, 101 pp. 3154-9 (2004)].
  • IMPDH inhibitors with improved pharmacological properties and selectivities.
  • Such inhibitors should have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, antiinflammatory agents, antifungal agents, antipsoriatic and anti-viral agents.
  • selective IMPDH inhibitors that can slow or block parasite and bacterial proliferation.
  • the present invention fulfills this need and has other related advantages.
  • One aspect of the present invention relates to compounds, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as inhibitors of IMPDH.
  • a compound of the invention selectively inhibits a parasitic IMPDH versus a host (e.g., mammalian) IMPDH.
  • the invention provides pharmaceutical compositions comprising one or more compounds of the invention.
  • the invention also relates to methods of treating various parasitic and bacterial infections in mammals.
  • the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.
  • FIG. 1 depicts triazole compounds 1-7 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 2 depicts triazole compounds 8-14 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 3 depicts triazole compounds 15-21 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 4 depicts triazole compounds 22-28 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 5 depicts triazole compounds 29-34 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 6 depicts triazole compounds 35-39 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 7 depicts a general scheme for the preparation of various 1,2,3-triazoles. Reagents and conditions: X and Y ⁇ N, CH, or CCl.
  • [R 1 Me]MeCH(OH)C ⁇ CH, 0° C., Ph 3 P, 10 min, DEAD, rt, 12 h;
  • [R 1 Et, R 2 ⁇ CO 2 Et] DIBAL, THF, ⁇ 78° C., 6 h;
  • FIG. 8 depicts the synthesis of 41 [R 1 Et, R 2 ⁇ CO 2 Et].
  • Reagents and conditions (a) (i) c-PrMgBr, THF, ⁇ 20° C., 2 h, (ii) Ph 3 P, CBr 4 , DCM, 0° C., 2 h; (b) 1-naphthol, K 2 CO 3 , DMF, rt, 2 h; (c) 3 M NaOH, THF:H 2 O (2:1), 80° C., 6 h.
  • FIG. 9 depicts a representative synthetic scheme for the formation of triazoles 51.
  • FIG. 11 depicts oxadiazole compound 52 and its IC 50 value against recombinant C. parvum IMPDH.
  • FIG. 12 depicts amide compounds 53-57 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 13 depicts amide compounds 58-67 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 14 depicts amide compounds 68-76 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 15 depicts amide and ester compounds 77-85 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 16 depicts amide compounds 86-95 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 17 depicts amide compounds 96-104 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 18 depicts amide compounds 105-113 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 19 depicts amide and ketone compounds 114-120 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 20 depicts amide compounds 121-122 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 21 depicts amide compounds 123-124 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 22 depicts amide compounds 125-129 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 23 depicts amide compounds 130-134 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 24 depicts compounds 135-140 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 25 depicts amide compounds 141-145 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 26 depicts compounds 146-148 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 27 depicts amide compounds 149-152 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 28 depicts amide compounds 153-156 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 29 depicts amide compounds 157-160 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 30 depicts amide compounds 161-162 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 31 depicts amide compounds 163-167 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 32 depicts amide compounds 168-172 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 33 depicts amide compounds 173-177 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 34 depicts amide, ester, and ketone compounds 178-185 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 35 depicts two syntheses of 188.
  • Reagents and conditions (a) (i) c-PrMgBr, THF, ⁇ 20° C., 2 h, (ii) Ph 3 P, CBr 4 , DCM, 0° C., 2 h; (b) 1-naphthol, K 2 CO 3 , DMF, rt, 2 h; (c) 3 M NaOH, THF:H 2 O (2:1), 80° C., 6 h; (d) 4-chloroaniline, 0° C., EDCI.HCl, rt, 12 h; (e) 4-chloroaniline, cat. DMAP, DCM, rt, 2 h; (f) 4-hydroxyquinoline, K 2 CO 3 , DMF, 0° C., rt, 12 h.
  • FIG. 37 depicts triazole compounds A111-A113 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 38 depicts triazole compounds A114-A119 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 39 depicts amide compounds C68-C70 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 40 depicts amide compounds C71-C85 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 41 depicts amide compounds C86-C100 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 42 depicts phthalazinone compounds D1-D18 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 43 depicts phthalazinone compounds D19-D36 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 44 depicts phthalazinone compounds D37-D54 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 45 depicts phthalazinone compounds D55-D61 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 46 depicts pyrazole compounds N1-N18 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 47 depicts pyrazole compounds N19-N26 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 48 depicts urea compounds P1-P15 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 49 depicts urea compounds P16-P32 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 50 depicts urea compounds P33-P51 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 51 depicts urea compounds P52-P68 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 52 depicts urea compounds P69-P80 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 53 depicts urea compounds P81-P97 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 54 depicts benzoxazole compounds Q1-Q15 and their respective IC 50 values against recombinant C. parvum IMPDH.
  • FIG. 55 tabulates inhibition of recombinant C. parvum IMPDH (CpIMPDH) and human IMPDH type 2 (hIMPDH2). b. ⁇ 20% inhibition at 50 ⁇ M; c. ⁇ 20% inhibition at 5 ⁇ M; d. ⁇ 10% inhibition at 5 ⁇ M; e. ⁇ 20% inhibition observed at 2 ⁇ M.
  • FIG. 56 tabulates the results of metabolic and plasma stability studies on various compounds of the invention.
  • FIG. 57 depicts validation of the T. gondii -CpIMPDH reporter parasite. Schematics of the routes to GMP for the wild-type T. gondii, T. gondii - ⁇ HXGPRT, and T. gondii -CpIMPDH are shown in A, D & G respectively. Genetic studies have shown that the salvage of adenosine via adenosine kinase is the predominant route to GMP for T. gondii and IMPDH catalyzes the rate limiting step of this pathway.
  • TgHXGPRT allows for the salvage of adenosine, adenine and guanosine such that the activity of TgHXGPRT is sufficient for parasite proliferation.
  • Several transporters for the uptake of nucleobases and nucleotides have been characterized in T. gondii .
  • C. parvum lacks HXGPRT and is dependent on the salvage of adenosine and thus the activity of CpIMPDH.
  • a single adenosine transporter has been identified in the genome of C. parvum . The T.
  • Hyp hypoxanthine
  • Xan xanthine
  • Gua guanine
  • Guo guanosine
  • Ade adenine
  • Ado adenosine
  • Ino inosine
  • AMP adenosine monophosphate
  • IMP inosine monophosphate
  • XMP xanthosine monophosphate
  • GMP guanosine monophosphate
  • HXGPRT hypoxanthine xanthine gunanine phosphoribosyltransferase
  • IMPDH IMP dehydrogenase, 1, adenine deaminase; 2, adenosine deaminase; 3, purine nucleoside phosphorylase; 4, adenosine kina
  • Panels B, E & H show parasite growth in the presence of 0 ⁇ M and 7.8 ⁇ M MPA for wild-type T. gondii, T. gondii -AHXGPRT, and T. gondii -CpIMPDH respectively.
  • Panels C, F, and I show parasite growth curves in the presence of 0 ⁇ M and 7.8 ⁇ M MPA, with the addition of 0.33 mM xanthine to the culture media, for wild-type T. gondii, T. gondii - ⁇ HXGPRT, and T. gondii -CpIMPDH respectively. Data are representative of two independent experiments.
  • FIG. 58 depicts an overview and validation of the high content imaging C. parvum growth assay.
  • A schematic representation of differential labelling of parasite and host.
  • B detail of an exemplary micrograph obtained through the screening routine. Numbers indicate object identifies after segmentation analysis.
  • Panel C shows a 2-fold titration of C. parvum oocysts where the top concentration was 1.2 ⁇ 10 6 oocysts per well.
  • panel D the ratio of the number of FITC-VVL labelled C. parvum parasites to DAPI labelled HCT-8 host cell nuclei was used to standardize each well and percent C. parvum growth (solid line) was normalized to parasites receiving DMSO alone.
  • FIG. 59 depicts the identification of derivatives with high potency and selectivity in the T. gondii -CpIMPDH model.
  • Panel A shows the EC 50 for a selection of compounds assayed in the T. gondii -CpIMPDH parasite model and demonstrates a range in compound selectivity and potency. Compounds were assayed in triplicate and growth inhibition was calculated on a day during the exponential phase of growth, by normalization to wells receiving DMSO alone. The EC 50 calculation was performed as described in FIG. 63 . Compounds A82, A89, A90, A92, A102, A103, A105, and A110 were selected for rescreening and the mean for at least 2 replicate experiments are shown.
  • Panel C shows percent host cell growth assayed using the pmaxGFP fluorescent HCT-8 cell line with compound at 12.5 ⁇ M and 25 ⁇ M.
  • GFP expressing HCT-8 cells were seeded at 4000 cells per well into 96-well plates and triplicate wells were spiked with test compound. Fluorescence was measured daily with a SpectraMax M22/M2e (Molecular Devices) plate reader (Ex 485, Em 530) for 7 days. Percent growth inhibition was calculated on a day during the exponential phase of growth, by normalization to wells receiving DMSO alone. A selection of compounds A89, A90 and A92 were selected for re-screening and the mean over at least two replicate experiments is shown.
  • FIG. 60 depicts the correlation between CpIMPDH enzyme inhibition and potency and selectivity in the T. gondii -CpIMPDH model.
  • a strong, positive correlation exists between the potency of CpIMPDH enzyme inhibition when assayed in the presence of BSA and inhibition of T. gondii -CpIMPDH proliferation (r ⁇ 0.94, p ⁇ 0.0001; panel B).
  • FIG. 61 depicts that compounds A103 and A110 are potent inhibitors of C. parvum growth.
  • C. parvum growth was determined using the HCl assay. The ratio of the number of FITC-VVL labelled C. parvum parasites to DAPI labelled HCT-8 host cell nuclei was used to standardize each well and percent C. parvum growth was normalised to parasites receiving DMSO alone.
  • Panels A and B show compounds A103 and A110 respectively (EC 50 ⁇ 0.8 ⁇ M). Data shows the mean of two independent experiments with triplicate wells.
  • FIG. 62 tabulates data for various compounds in enzyme assays (in the absence and presence of BSA), surrogate T. gondii model assay, host cell growth and tissue culture model of C. parvum infection. N.A., not applicable; N.D., not determined.
  • a. Selectivity T. gondii -CpIMPDH EC 50 versus wild-type T. gondii EC 50 ; b. highest concentration tested; c. Maurya et al; d. lowest concentration tested; e. Umejiego et al.; f. qPCR assay.
  • FIG. 63 depicts an overview of obtaining an EC 50 for T. gondii growth.
  • Fluorescent T. gondii parasites are seeded into 96-well plates and spiked with test compound. Fluorescence is measured daily with a SpectraMax M22/M2e (Molecular Devices) plate reader for 6-7 days. The fluorescence readings on a day during the exponential phase of the growth curve, for example day 4 in panel A, are used to calculated percent growth inhibition.
  • FIG. 64 shows results of various compounds in the surrogate T. gondii model.
  • Panel A shows the EC 50 for a selection of compounds assayed in the T. gondii -CpIMPDH parasite model. Compounds were assayed in triplicate and growth inhibition was calculated on a day during the exponential phase of growth, by normalization to wells receiving DMSO alone. The EC 50 calculation was performed as described in figure S2. Note the highest concentration tested in panel A was for compound A30 was 20 ⁇ M.
  • Panel B shows percent host cell growth assayed using the pmaxGFP fluorescent HCT-8 cell line with compound at 25 ⁇ M and 50 ⁇ M.
  • GFP expressing HCT-8 cells were seeded at 4000 cells per well into 96-well plates and triplicate wells were spiked with test compound. Fluorescence was measured daily with a SpectraMax M22/M2e (Molecular Devices) plate reader (Ex 485, Em 530) for 7 days. Percent growth inhibition was calculated on a day during the exponential phase of growth, by normalization to wells receiving DMSO alone.
  • FIG. 65 depicts the selectivity of various compounds in the surrogate Toxo/CpIMPDH assay.
  • FIG. 66 tabulates activity levels of various compounds; the surrogate Toxoplasma model is predictive for anti- Cryptosporidium activity.
  • FIG. 67 tabulates the inhibition of various IMPDHs by compounds A-H. Cp, C. parvum ; Hp, Helicobacter pylori ; Bb, Borrelia burgdorferi ; Sp, Streptococcus pylori ; ECIMPDH S250A/L444Y, Escherichia coli IMPDH containing an alanine residue at serine-240 and a leucine residue at tyrosine-444. These compounds (100 ⁇ M) do not inhibit IMPDHs from E. coli, Leishmania donovanii and Tritrichomonas foetus . “Intrinsic” values (adjusted for the competition with the mobile flap) are shown in parentheses.
  • FIG. 68 depicts the IMPDH reaction: a. Chemical mechanism: a conserved Cys attacks C2 of IMP and hydride is transferred to NAD + producing the covalent intermediate E-XMP*. E-XMP* is hydrolyzed with a conserved Arg residue acting as a general base to produce XMP. b. The hydride transfer reaction proceeds in an open enzyme conformation. After NADH departs, a mobile flap folds into the NAD site, carrying the catalytic Arg into the active site Inhibitors compete with the flap, so the equilibrium between open and closed states is a determinant of inhibitor affinity. c. Phylogenetic tree of IMPDHs.
  • FIG. 69 depicts that C91 inhibits H. pylori growth.
  • CFU colony forming units. Filled circles, DMSO alone.
  • C91 concentrations open circles, 2 ⁇ M; closed squares, 7 ⁇ M; open squares, 20 ⁇ M; closed triangles, 60 ⁇ M; open triangles, 200 ⁇ M.
  • FIG. 70 depicts the x-ray crystal structure of CpIMPDH with IMP and C64 shown from two different perspectives.
  • the electron density map prior to C64 modeling with coefficients 2Fo-Fc is contoured to 1 ⁇ and shown as a slate cage.
  • the electron density map prior to C64 modeling with coefficients Fo-Fc is contoured to 3 ⁇ .
  • Bromine K-edge peak anomalous dispersion map is contoured to 4 ⁇ .
  • FIG. 71 depicts the C64 binding pocket of CpIMPDH superposed with human IMPDH2. CpIMPDH residues are labeled.
  • One aspect of the present invention relates to compounds, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as inhibitors of IMPDH.
  • a compound of the invention selectively inhibits a parasitic or bacterial IMPDH versus a host (e.g., mammalian) IMPDH.
  • the present invention relates to selective inhibition of Cryptosporidium IMPDH in the presence of human inosine-5′-monophosphate-dehydrogenase (IMPDH type I and type II).
  • the invention provides pharmaceutical compositions comprising one or more compounds of the invention.
  • the invention also relates to methods of treating various parasitic and bacterial infections in mammals.
  • the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.
  • IMPDH-mediated disease refers to any disease state in which the IMPDH enzyme plays a regulatory role in the metabolic pathway of that disease.
  • IMPDH-mediated disease include transplant rejection and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as other inflammatory diseases, cancer, viral replication diseases and vascular diseases.
  • the compounds, compositions and methods of using them of the invention may be used in the treatment of transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel and skin allografts and heart valve xenografts) and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitus), lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anemia, idiopathic adrenal insufficiency, polyglandular autoimmune syndrome, and glomerul
  • IMPDH enzymes are also known to be present in bacteria, fungi, and protozoans and thus may regulate microbial growth.
  • the IMPDH-inhibitor compounds, compositions and methods described herein may be useful as antibacterials, antifungals, and/or antiprotozoans, either alone or in combination with other anti-microbial agents.
  • Microbial inhibition can be measured by various methods, including, for example, IMPDH HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD), IMPDH spectrophotometric assays (measuring enzymatic production of NADH from NAD or XMP from IMP), IMPDH fluorometric assays (measuring enzymatic production of NADH from NAD), IMPDH radioassays (measuring enzymatic production of radiolabeled XMP from radiolabeled IMP or tritium release into water from 2 ⁇ 3 H-IMP).
  • IMPDH HPLC assays measuring enzymatic production of XMP and NADH from IMP and NAD
  • IMPDH spectrophotometric assays measuring enzymatic production of NADH from NAD or XMP from IMP
  • IMPDH fluorometric assays measuring enzymatic production of NADH from NAD
  • the inventive compounds are capable of targeting and selectively inhibiting the IMPDH enzyme in bacteria. It is known that knocking out the IMPDH gene makes some bacteria avirulent, while has no effect on others. The effectiveness probably depends on which salvage pathways are operational in a given bacteria, and the environmental niche of the infection. It has been shown that IMPDHs from H. pylori, S. pyogenes and B. burgdorferi are sensitive to the inhibitors of the invention, and that the growth of H. pylori is blocked by inhibitors of the invention.
  • Organisms belonging to these genera are responsible for illnesses such as ulcers and acid reflux ( H. pylori ), Lyme disease ( B. burgdorferi ), infection ( S. pyogenes ), food poisoning ( C. jejuni and A. butzleri ), abscesses ( B. capillosis ), periodontitis ( F. nucleatum ), skin ulcers ( F. nucleatum ), Lemierre's syndrome ( F.
  • these compounds are capable of targeting and selectively inhibiting the IMPDH enzyme in fungi, as evidenced by the mycophenolic acid sensitivity of Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans, Aspergillus flavus and Trichophyton.
  • the inventive compounds are capable of targeting and selectively inhibiting the IMPDH enzyme in protozoans, such as Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Leishmania and Trypanosoma .
  • protozoans such as Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Leishmania and Trypanosoma .
  • these compounds are capable of targeting and selectively inhibiting the IMPDH enzyme in Cryptosporidium parvum and other Cryptosporidium species.
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula I:
  • R 1 is hydrogen, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl
  • R 2 is hydrogen or alkyl
  • R 3 is hydrogen or alkyl
  • Y 1 is absent, O, or NR 4 ;
  • Y 2 is absent, O, NR 4 , alkylene, —(CH 2 ) m —O—(CH 2 ) p —, —(CH 2 ) m —NR 4 —(CH 2 ) p —, —(CH 2 ) m —C( ⁇ O)—(CH 2 ) p —, —(CH 2 ) m C( ⁇ O)NR 4 —(CH 2 ) p —, or —(CH 2 ) m C( ⁇ O)O—(CH 2 ) p —;
  • n 0, 1, 2, 3, or 4;
  • R 4 is hydrogen or alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0, 1, or 2;
  • the invention relates to any one of the aforementioned compounds, wherein Y 1 is O or absent.
  • the invention relates to any one of the aforementioned compounds, wherein Y 1 is O.
  • the invention relates to any one of the aforementioned compounds, wherein Y 1 is absent.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is aryl or hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is aryl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is phenyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein n is 1, 2, 3, or 4.
  • the invention relates to any one of the aforementioned compounds, wherein n is 0 or 1.
  • the invention relates to any one of the aforementioned compounds, wherein n is 1.
  • the invention relates to any one of the aforementioned compounds, wherein n is 0.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is hydrogen or alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is methyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is ethyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is i-propyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 and an instance of R 2 taken together with the carbon atoms to which they are attached form a 5- or 6-membered aryl ring.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 and an instance of R 2 taken together with the carbon atoms to which they are attached form a 6-membered aryl ring.
  • the invention relates to any one of the aforementioned compounds, wherein R 3 is hydrogen or alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein Y 2 is absent, —(CH 2 ) m C( ⁇ O)NR 4 —(CH 2 ) p —, or —(CH 2 ) m C( ⁇ O)O—(CH 2 ) p —.
  • the invention relates to any one of the aforementioned compounds, wherein Y 2 is absent.
  • the invention relates to any one of the aforementioned compounds, wherein Y 2 is —(CH 2 ) m C( ⁇ O)NR 4 —(CH 2 ) p —.
  • the invention relates to any one of the aforementioned compounds, wherein Y 2 is —(CH 2 ) m C( ⁇ O)NR 4 —(CH 2 ) p —; R 4 is hydrogen; m is 1; and p is 0.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano; and q is 0 to 5 inclusive.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is selected from the group consisting of halo, alkoxy, haloalkyloxy, alkylthio, amido, and cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is bromo
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkoxy
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is methoxy
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is haloalkyloxy.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is trifluoromethoxy.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkylthio.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is methylthio
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is cyano
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo; and one instance of R 5 is cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo; and one instance of R 5 is amido.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro; and one instance of R 5 is cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • q is 0 to 5, inclusive;
  • Z is —N— or —CH—;
  • R 5 is halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano; and R 6 is hydrogen or alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula II:
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula III:
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula IV:
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula V:
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula VI:
  • the invention relates to any one of the aforementioned compounds, wherein X is absent, methylene, —NH—, —SO 2 —, or —CH ⁇ N—.
  • the invention relates to any one of the aforementioned compounds, wherein X is absent.
  • the invention relates to any one of the aforementioned compounds, wherein X is methylene.
  • the invention relates to any one of the aforementioned compounds, wherein X is —NH—.
  • the invention relates to any one of the aforementioned compounds, wherein X is —SO 2 —.
  • the invention relates to any one of the aforementioned compounds, wherein X is —CH ⁇ N—.
  • the invention relates to any one of the aforementioned compounds, wherein q is 0.
  • the invention relates to any one of the aforementioned compounds, wherein q is 1.
  • the invention relates to any one of the aforementioned compounds, wherein q is 1; and R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein q is 1; and R 5 is bromo.
  • the invention relates to any one of the aforementioned compounds, wherein Z is —N ⁇ .
  • the invention relates to any one of the aforementioned compounds, wherein n is 1, 2, 3, or 4.
  • the invention relates to any one of the aforementioned compounds, wherein n is 1 or 2.
  • the invention relates to any one of the aforementioned compounds, wherein n is 1.
  • the invention relates to any one of the aforementioned compounds, wherein n is 2.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is hydrogen or alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is methyl, ethyl, n-propyl, or i-propyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein R 3 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is amido, alkoxy, halo, haloalkyl, aryl, haloaryl, alkyl, hydroxy, alkylthio, sulfonyl, haloalkoxy, or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkoxy or halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is amido, halo, or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, hydroxy, or alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkoxycarbonyl
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 2 is alkyl
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 2 is methyl
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula VII:
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula VIII:
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula IX:
  • R 2 is hydrogen or alkyl
  • n 0, 1, or 2;
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 2 is methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein m is 0 or 1.
  • the invention relates to any one of the aforementioned compounds, wherein m is 0.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is amido, alkoxy, halo, haloalkyl, aryl, haloaryl, alkyl, hydroxy, alkylthio, sulfonyl, haloalkoxy, or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkoxy or halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is amido, halo, or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is amido
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula X:
  • n 0, 1, 2, or 3;
  • X is absent, O, S, or NH
  • the invention relates to any one of the aforementioned compounds, wherein one occurrence of m is 0; and one occurrence of m is 1.
  • the invention relates to any one of the aforementioned compounds, wherein one occurrence of m is 0; and one occurrence of m is 2.
  • the invention relates to any one of the aforementioned compounds, wherein one occurrence of m is 0; and one occurrence of m is 3.
  • the invention relates to any one of the aforementioned compounds, wherein X is O.
  • the invention relates to any one of the aforementioned compounds, wherein X is S.
  • the invention relates to any one of the aforementioned compounds, wherein X is NH.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano; and q is 0 to 5 inclusive.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is selected from the group consisting of halo, alkoxy, haloalkyloxy, alkylthio, amido, and cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is bromo
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkoxy
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is methoxy
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is haloalkyloxy.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is trifluoromethoxy.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is alkylthio.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is methylthio
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is cyano
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo or cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo; and one instance of R 5 is cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo; and one instance of R 5 is amido.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro; and one instance of R 5 is cyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is chloro
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XI:
  • n 0, 1, or 2;
  • R 2 is hydrogen or alkyl
  • R 3 is hydrogen or alkyl
  • the invention relates to any one of the aforementioned compounds, wherein m is 1.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1 or 2; and R 2 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1 or 2; and R 2 is alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1 or 2; and R 2 is methyl.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulihydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XII:
  • n 0, 1, or 2;
  • R 2 is hydrogen or alkyl
  • the invention relates to any one of the aforementioned compounds, wherein m is 0.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1 or 2; and R 2 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1 or 2; and R 2 is alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, or isocyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heterocycloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulihydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, oxime, or isocyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula XIII:
  • X is absent or 0
  • n 0, 1, or 2;
  • R 2 is hydrogen or alkyl
  • the invention relates to any one of the aforementioned compounds, wherein X is absent.
  • the invention relates to any one of the aforementioned compounds, wherein X is O.
  • the invention relates to any one of the aforementioned compounds, wherein m is 0.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1; and R 2 is hydrogen.
  • the invention relates to any one of the aforementioned compounds, wherein m is 1; and R 2 is alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heterocycloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulihydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, oxime, or isocyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heterocycloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulihydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, oxime, or isocyano.
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to any one of the aforementioned compounds, wherein
  • the invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • the compounds of the invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are included in the present invention, unless expressly excluded.
  • Each stereogenic carbon may be of the R or S configuration.
  • the compounds of the invention described above may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the invention relates to a pharmaceutical composition, comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle; and any one of the aforementioned compounds.
  • the invention relates to any one of the aforementioned compositions, further comprising an antimicrobial agent.
  • the invention relates to any one of the aforementioned compositions, further comprising an antibiotic, antifungal, or antiprotozoal agent.
  • the invention relates to any one of the aforementioned compositions, further comprising an antibiotic agent selected from the group consisting of vancomycin, metronidazole, amoxicillin, ciprofloxacin, doxycycline, gentamicin and clindamycin.
  • an antibiotic agent selected from the group consisting of vancomycin, metronidazole, amoxicillin, ciprofloxacin, doxycycline, gentamicin and clindamycin.
  • the invention relates to any one of the aforementioned compositions, further comprising an antifungal selected from the group consisting of terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, voriconazole, nikkomycin Z, caspofungin, micafungin (FK463), anidulafungin (LY303366), amphotericin B (AmB), and nystatin.
  • an antifungal selected from the group consisting of terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, voriconazole, nikkomycin Z, caspofungin, micafungin (FK463), anidulafungin (LY303366), amphotericin B (AmB), and nystatin.
  • the invention relates to any one of the aforementioned compositions, further comprising an antiprotozoal agent selected from the group consisting of eflornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
  • an antiprotozoal agent selected from the group consisting of eflornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and tinidazole.
  • the invention relates to any one of the aforementioned compositions, further comprising an immunosuppression agent.
  • the invention relates to any one of the aforementioned compositions, further comprising an immunosuppression agent selected from the group consisting of cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
  • an immunosuppression agent selected from the group consisting of cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
  • the invention relates to any one of the aforementioned compositions, further comprising an anti-cancer agent.
  • the invention relates to any one of the aforementioned compositions, further comprising an anti-cancer agent selected from the group consisting of cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, teniposide, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxanthenes.
  • an anti-cancer agent selected from the group consisting of cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, teniposide, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxanthenes.
  • the invention relates to any one of the aforementioned compositions, further comprising an anti-viral agent.
  • the invention relates to any one of the aforementioned compositions, further comprising an anti-viral agent selected from the group consisting of cytovene, ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddI, AZT, and acyclovir.
  • an anti-viral agent selected from the group consisting of cytovene, ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddI, AZT, and acyclovir.
  • the invention relates to any one of the aforementioned compositions, further comprising an anti-vascular hyperproliferative agent.
  • the invention relates to any one of the aforementioned compositions, further comprising an anti-vascular hyperproliferative selected from the group consisting of HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate.
  • HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate.
  • the compounds of the invention are defined to include pharmaceutically acceptable salts or prodrugs thereof.
  • a “pharmaceutically acceptable salt or prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
  • Particularly favored prodrugs are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Exemplary prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of the compounds of the invention.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pec
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), and ammonium salts.
  • alkali metal e.g., sodium
  • alkaline earth metal e.g., magnesium
  • ammonium salts e.g., sodium
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • the invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises any one of the aforementioned compounds or a pharmaceutically acceptable salt thereof; an additional agent selected from the group consisting of an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, and an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein the pharmaceutical composition comprises any one of the aforementioned compounds or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein the pharmaceutical composition optionally comprises an additional agent selected from the group consisting of an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, and an anti-vascular hyperproliferation compound.
  • an immunosuppressant selected from the group consisting of an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, and an anti-vascular hyperproliferation compound.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d.alpha.-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, poly
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of any one of the aforementioned compounds.
  • compositions of the invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as those described in Pharmacopeia Helvetica, Ph.
  • Helv., or a similar alcohol, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of the invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of the invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of the invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of the invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxy-ethylene polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of the invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.
  • compositions of the invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, or between about 0.5 and about 75 mg/kg body weight per day, of the IMPDH inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of IMPDH-mediated disease or infection.
  • the pharmaceutical compositions of the invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w). Such preparations contain from about 20% to about 80% active compound.
  • compositions of the invention comprise a combination of an IMPDH inhibitor of the invention and one or more additional therapeutic or prophylactic agents
  • both the IMPDH inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, or between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition.
  • a maintenance dose of a compound, composition or combination of the invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the invention relates to a pharmaceutical composition for treatment or prevention of a protozoan infection, comprising a pharmaceutically acceptable carrier, adjuvant or vehicle and at least one of the aforementioned compounds, or a pharmaceutically acceptable salt or prodrug thereof.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein said protozoan infection is caused by a protozoan selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.
  • a protozoan selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein said protozoan infection is caused by a protozoan selected from the genus Cryptosporidium.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein said protozoan infection is caused by Cryptosporidium parvum.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein the pharmaceutical composition further comprises an antimicrobial agent, such as an antibiotic, antifungal, or antiprotozoal agent.
  • an antimicrobial agent such as an antibiotic, antifungal, or antiprotozoal agent.
  • antibiotic agents include, but are not limited to, vancomycin, metronidazole, amoxicillin, ciprofloxacin, doxycycline, gentamicin and clindamycin.
  • antifungal examples include, but are not limited to, terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, voriconazole, nikkomycin Z, caspofungin, micafungin (FK463), anidulafungin (LY303366), amphotericin B (AmB), and nystatin.
  • antiprotozoal agents include, but are not limited to, eflornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and timidazole.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, wherein the pharmaceutical composition is used for treatment or prevention of an IMPDH-mediated disease, and comprises a pharmaceutically acceptable carrier, adjuvant or vehicle and at least one aforementioned compound.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, further comprising an immunosuppression agent.
  • additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon, and mizoribine.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, further comprising an anti-cancer agent.
  • anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, teniposide, taxol, colchicine, cyclosporin A, phenothiazines, interferon, and thioxanthenes.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, further comprising an anti-viral agent.
  • anti-viral agents include, but are not limited to, cytovene, ganciclovir, trisodium phosphonoformate, Ribavirin, d4T, ddI, AZT, and acyclovir.
  • the invention relates to any one of the aforementioned pharmaceutical compositions, further comprising an anti-vascular hyperproliferative agent.
  • anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin, and 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate.
  • HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin, and 5-(3′-pyr
  • the invention relates to a method of killing or inhibiting the growth of a microbe, comprising the step of contacting said microbe with an effective amount of any one of the aforementioned compounds.
  • the invention relates to any one of the aforementioned methods, wherein said microbe is a protozoon, a bacterium, or a fungus.
  • the invention relates to any one of the aforementioned methods, wherein said microbe is a protozoon or a bacterium selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Salmonella, Shigella, Yersinia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
  • a bacterium selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Gi
  • the invention relates to any one of the aforementioned methods, wherein said microbe is a protozoon; and said protozoon is selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.
  • the invention relates to any one of the aforementioned methods, wherein said protozoon is selected from the genus Cryptosporidium.
  • the invention relates to any one of the aforementioned methods, wherein said protozoon is Cryptosporidium parvum.
  • the invention relates to any one of the aforementioned methods, wherein said microbe is a bacterium; and said bacterium is selected from the group consisting of the genera Helicobacter, Borrelia, Salmonella, Shigella, Yersinia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
  • the invention relates to a method of treating or preventing a microbial infection in a mammal, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.
  • the invention relates to a method of treating or preventing a parasitic infection in a mammal comprising the step of administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.
  • the invention relates to any one of the aforementioned methods, wherein said microbial infection is caused by a protozoon, a bacterium, or a fungus.
  • the invention relates to any one of the aforementioned methods, wherein said microbial infection is caused by a protozoon or a bacterium selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Salmonella, Shigella, Yersinia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
  • a protozoon or a bacterium selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neo
  • the invention relates to any one of the aforementioned methods, wherein said microbial infection is caused by a protozoon; and said protozoon is selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.
  • the invention relates to any one of the aforementioned methods, wherein said protozoon is selected from the genus Cryptosporidium.
  • the invention relates to any one of the aforementioned methods, wherein said microbial infection is caused by Cryptosporidium parvum.
  • the invention relates to any one of the aforementioned methods, wherein said microbe is a bacterium; and said bacterium is selected from the group consisting of the genera Helicobacter, Borrelia, Salmonella, Shigella, Yersinia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
  • the invention relates to any one of the aforementioned methods, further comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of an antimicrobial agent.
  • the invention relates to any one of the aforementioned methods, wherein said antimicrobial agent is an antibiotic. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein said antimicrobial agent is an antibiotic. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein said antibiotic agent is selected from the group consisting of vancomycin, metronidazole, amoxicillin, ciprofloxacin, doxycycline, gentamicin, and clindamycin.
  • the invention relates to any one of the aforementioned methods, wherein said antimicrobial agent is an antifungal. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein said antifungal agent is selected from the group consisting of terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, voriconazole, nikkomycin Z, caspofungin, micafungin (FK463), anidulafungin (LY303366), amphotericin B (AmB), and nystatin.
  • said antifungal agent is selected from the group consisting of terbinafine, flucytosine, fluconazole, itraconazole, ketoconazole, voriconazole, nikkomycin Z, caspofungin, micafungin (FK463), anidulafungin (LY303366), amphotericin B (AmB), and nystatin.
  • the invention relates to any one of the aforementioned methods, wherein said antimicrobial agent is an antiparasitic.
  • said antiparasitic agent is selected from the group consisting of eflornithine, furazolidone, melarsoprol, metronidazole, ornidazole, paromomycin sulfate, pentamidine, pyrimethamine, and timidazole.
  • the invention relates to a method of treating or preventing an IMPDH-mediated disease in a mammal, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of any one of the aforementioned compounds.
  • the pharmaceutical composition only comprises the IMPDH inhibitor of the invention as the active component, such methods may additionally comprise the step of administering to a mammal in need thereof a therapeutically effective amount of an agent selected from an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, or an anti-vascular hyperproliferation compound.
  • additional agents may be administered to the mammal prior to, concurrently with, or following the administration of the IMPDH inhibitor composition.
  • the invention relates to any one of the aforementioned methods, wherein the IMPDH-mediated disease is transplant rejection, graft versus host disease, rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitus, lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome, pernicious or immunohaemolytic anemia, idiopathic adrenal insufficiency, polyglandular autoimmune syndrome, glomerulonephritis, scleroderma, lichen planus, viteligo, autoimmune thyroiditis, alveolitis, HTLV-1, HTLV-2, HIV-1, HIV-2,
  • the invention relates to any one of the aforementioned methods, further comprising the step of co-administering to a mammal in need thereof a therapeutically effective amount of an agent selected from the group consisting of an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, and an anti-vascular hyperproliferation compound.
  • an agent selected from the group consisting of an antiinflammatory agent, immunosuppressant, an anti-cancer agent, an anti-viral agent, and an anti-vascular hyperproliferation compound.
  • the invention relates to any one of the aforementioned methods, wherein the method is useful in suppressing an immune response in a mammal.
  • diseases including, transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel and skin allografts and heart valve xenografts), graft versus host disease, and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitus), lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eye uveitis, hepatitis, Grave's disease, Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), per
  • transplant rejection e.g., kidney,
  • the invention relates to any one of the aforementioned methods, wherein the method comprises the step of administering to the mammal a composition comprising any one of the aforementioned compounds and a pharmaceutically acceptable adjuvant. In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising the step of administering to a mammal in need thereof a composition comprising an additional immunosuppressant and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to a mammal in need thereof a composition comprising a compound of the invention; an additional immunosuppressive agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, wherein the method is useful for inhibiting viral replication in a mammal.
  • Such methods are useful in treating or preventing, DNA and RNA viral diseases caused by, for example, HTLV-1 and HTLV-2, HIV-1 and HIV-2, nasopharyngeal carcinoma virus, HBV, HCV, HGV, yellow fever virus, dengue fever virus, Japanese encephalitis virus, human papilloma virus, rhinoviruses and Herpes viruses, such as Epstein-Barr, cytomegaloviruses and Herpes Simplex, Types 1 and 2, or Type 6. See U.S. Pat. No. 5,380,879 (incorporated by reference).
  • the invention relates to any one of the aforementioned methods, wherein the method comprises the step of administering to the mammal a composition comprising any one of the aforementioned compounds, and a pharmaceutically acceptable adjuvant. In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising the step of administering to a mammal in need thereof a composition comprising an additional anti-viral agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to a mammal in need thereof a composition comprising any one of the aforementioned compounds; an additional anti-viral agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, wherein the method is useful for inhibiting vascular cellular hyperproliferation in a mammal.
  • Such methods are useful in treating or preventing diseases, including, restenosis, stenosis, artherosclerosis and other hyperproliferative vascular disease.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to the mammal a composition comprising any one of the aforementioned compounds, and a pharmaceutically acceptable adjuvant. In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a composition comprising an additional anti-vascular hyperproliferative agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a composition comprising any one of the aforementioned compounds; an additional anti-vascular hyperproliferative agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, wherein the method is useful for inhibiting tumors and cancer in a mammal.
  • Such methods are useful in treating or preventing diseases, including, tumors and malignancies, such as lymphoma, leukemia and other forms of cancer.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to the mammal a therapeutically effective amount of a composition comprising any one of the aforementioned compounds, and a pharmaceutically acceptable adjuvant. In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a composition comprising an additional anti-tumor or anti-cancer agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to a mammal in need thereof a composition comprising any one of the aforementioned compounds; a therapeutically effective amount of an additional anti-tumor or anti-cancer agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, wherein the method is useful for inhibiting inflammation and inflammatory diseases in a mammal.
  • Such methods are useful in treating or preventing diseases, including, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome.
  • the invention relates to any one of the aforementioned methods, comprising the step of administering to the mammal a composition comprising a therapeutically effective amount of any one of the aforementioned compounds, and a pharmaceutically acceptable adjuvant. In certain embodiments, the invention relates to any one of the aforementioned methods, further comprising the step of administering to a mammal in need thereof a composition comprising a therapeutically effective amount of an antiinflammatory agent and a pharmaceutically acceptable adjuvant.
  • the invention relates to any one of the aforementioned methods, wherein the mammal is a primate, a bovine, an ovine, an equine, a porcine, a rodent, a feline, a mustelid, or a canine
  • the invention relates to any one of the aforementioned methods, wherein the mammal is a primate.
  • the invention relates to any one of the aforementioned methods, wherein the mammal is a human.
  • a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 80 or fewer carbon atoms in its backbone (e.g., C 1 -C 80 for straight chain, C 3 -C 80 for branched chain), and alternatively, about 30 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • fluoroalkyl denotes an alkyl where one or more hydrogens have been replaced with fluorines.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulihydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, trifluoromethyl, cyano, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively.
  • 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • heterocyclyl refers to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, trifluoromethyl, cyano, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl,
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • ring systems refers to 5 or 6 member monocyclic rings, 8, 9 and 10 membered bicyclic ring structures, and 11, 12, 13 and 14 membered tricyclic ring structures, wherein each bond in each ring may be possess any degree of saturation that is chemically feasible. When such structures contain substituents, those substituents may be at any position of the ring system, unless otherwise specified. As specified, such ring systems may optionally comprise up to 4 heteroatoms selected from N, O or S. Those heteroatoms may replace any carbon atoms in these ring systems as long as the resulting compound is chemically stable.
  • the term “monocyclic” ring system, as used herein, includes saturated, partially unsaturated and fully unsaturated ring structures.
  • the term “bicyclic” ring system, as used herein, includes systems wherein each ring is independently saturated, partially unsaturated and fully unsaturated.
  • Examples of monocyclic and bicyclic ring systems useful in the compounds of the invention include, but are not limited to, cyclopentane, cyclopentene, indane, indene, cyclohexane, cyclohexene, cyclohexadiene, benzene, tetrahydronaphthalene, decahydronaphthalene, naphthalene, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3,4-tetrazine, 1,2,4,5-tetrazine, 1,2,3,4-tetrahydroquinoline, quinoline, 1,2,3,4-tetrahydroisoquinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,5-naphthyridine, 1,6-
  • heterocycles may be attached to the rest of the compound by any atom of the heterocycle which results in the creation of a stable structure.
  • ring atom refers to a backbone atom that makes up the ring. Such ring atoms are selected from C, N, O or S and are bound to 2 or 3 other such ring atoms (3 in the case of certain ring atoms in a bicyclic ring system).
  • ring atom does not include hydrogen.
  • nitro is art-recognized and refers to —NO 2 ;
  • halogen is art-recognized and refers to —F, —Cl, —Br or —I;
  • sulfhydryl is art-recognized and refers to —SH;
  • hydroxyl means —OH;
  • sulfonyl is art-recognized and refers to —SO 2 ⁇ .
  • Halide designates the corresponding anion of the halogens
  • pseudohalide has the definition set forth on page 560 of “Advanced Inorganic Chemistry” by Cotton and Wilkinson, that is, for example, monovalent anionic groups sufficiently electronegative to exhibit a positive Hammett sigma value at least equaling that of a halide (e.g., CN, OCN, SCN, SeCN, TeCN, N 3 , and C(CN) 3 ).
  • a halide e.g., CN, OCN, SCN, SeCN, TeCN, N 3 , and C(CN) 3 .
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH 2 ) m —R61, or R50 and R51 or R52, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH 2 ) m —R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
  • R50 is as defined above
  • R54 represents a hydrogen, an alkyl, an alkenyl or —(CH 2 ) m —R61, where m and R61 are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the “alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S—(CH 2 ) m —R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 and R56 represents a hydrogen, an alkyl, an alkenyl, —(CH 2 ) m —R61 or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or —(CH 2 ) m —R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an “ester.”
  • X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a “carboxylic acid.”
  • R55 is a hydrogen
  • the formula represents a “formate.” In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiocarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a “thioester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a “thiolcarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a “thioformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a “ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an “aldehyde” group.
  • carbamoyl refers to —O(C ⁇ O)NRR′, where R and R′ are independently H, aliphatic groups, aryl groups or heteroaryl groups.
  • oxo refers to a carbonyl oxygen ( ⁇ O).
  • oxime and “oxime ether” are art-recognized and refer to moieties that may be represented by the general formula:
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH 2 ) m —R61.
  • the moiety is an “oxime” when R is H; and it is an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or —(CH 2 ) m —R61.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH 2 ) m —R61, where m and R61 are described above.
  • R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • R57 is as defined above.
  • sulfamoyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • sulfonyl is art-recognized and refers to a moiety that may be represented by the general formula:
  • R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • sulfoxide is art-recognized and refers to a moiety that may be represented by the general formula:
  • phosphoryl is art-recognized and may in general be represented by the formula:
  • Q50 represents S or O
  • R59 represents hydrogen, a lower alkyl or an aryl.
  • the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:
  • Q50 and R59 each independently, are defined above, and Q51 represents O, S or N.
  • Q50 is S
  • the phosphoryl moiety is a “phosphorothioate.”
  • R60 represents a lower alkyl or an aryl.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • selenoalkyl is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto.
  • exemplary “selenoethers” which may be substituted on the alkyl are selected from one of —Se-alkyl, —Se-alkenyl, —Se-alkynyl, and —Se—(CH 2 ) m —R61, m and R61 being defined above.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • treating refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated with a particular disorder.
  • patient refers to a mammal, including a human.
  • reaction mixture was quenched with 1N HCL to a pH ⁇ 7 and then extracted with chloroform.
  • the resulting material (360 mg, 1.58 mmol) was dissolved in anhydrous THF and cooled to ⁇ 78° C. Next, n-BuLi (121 mg, 1.90 mmol) was gradually added and the resulting solution stirred for 2 h at ⁇ 78° C. The mixture was quenched with water (50 mL), allowed to stir at room temperature for 30 min, and then extracted with ethyl acetate (3 ⁇ 100 mL).
  • Inhibitors at varying concentrations were incubated with 10 nM C. parvum in assay buffer for 10 min at room temperature.
  • the reaction was initiated by the addition of NAD and IMP for final concentrations of 300 ⁇ M and 150 ⁇ m, respectively.
  • Selectivity was measured against human type II and T. foetus IMPDH at 25° C. in assay buffer.
  • the former was assayed in the presence of 300 ⁇ M NAD + , 40 ⁇ M IMP and 160 nM human type II IMPDH, and the latter in the presence of 300 ⁇ M NAD + , 20 ⁇ M IMP and 28 nM T. foetus IMPDH.
  • IC 50 values of various compounds of the invention were determined for recombinant IMPDHs from H. pylori, B. burgdorferi , and S. pyogenes.
  • Cryptosporidium parvum is a potential bio-warfare agent, an important AIDS pathogen and a major cause of diarrhea and malnutrition.
  • This parasite relies on inosine 5′-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides and inhibition of this enzyme blocks parasite proliferation.
  • IMPDH inosine 5′-monophosphate dehydrogenase
  • Cryptosporidium spp. are a major cause of the “vicious cycle” of diarrhea and malnutrition in the developing world and a potential bioterrorism agent. This disease is prolonged and life-threatening in immuno-compromised patients.
  • the parasite obtains guanine nucleotides via a streamlined pathway that requires inosine 5′-monophosphate dehydrogenase (IMPDH).
  • IMPDH inosine 5′-monophosphate dehydrogenase
  • the gene encoding CpIMPDH appears to have been obtained from a bacteria via lateral gene transfer; we have exploited this unexpected divergence of parasite and host enzymes to identify CpIMPDH-specific inhibitors in a high throughput screen.
  • x-ray crystal structures of CpIMPDH that explain the selectivity of one inhibitor series and use this information to design more potent and selective analogs.
  • Recombinant CpIMPDH was purified as described previously and crystallized using the hanging drop vapor diffusion method.
  • Protein solution (4 mg/mL IMPDH, 50 mM Tris-HCl, pH 7.5, 150 mM KCl, 5% glycerol and 2 mM DTT) was mixed with well solution (34% PEG 4000, 25 mM sodium acetate and 100 mM Tris-HCl, pH 8.5) in a 1:1 ratio.
  • Data were collected from a single crystal at 100K at beamline 8-BM at Advanced Photon Source (Argonne National Laboratory, Argonne, Ill.). The crystals had the symmetry of space group P2 1 2 1 2.
  • the asymmetric unit contains one tetramer, which is the active form of IMPDH.
  • C64 binds in an unprecedented fashion.
  • Inhibitors of human IMPDH2 such as mycophenolic acid and merimepodib bind in the nicotinamide subsite, stacking against the purine ring of IMP in a parallel fashion, and extend either into the NAD site or into a pocket adjacent the active site but within the same monomer.
  • the thiazole ring of C64 stacks against the purine ring of IMP perpendicularly, and the remainder of C64 extends across the subunit interface into a pocket in the adjacent monomer, where the bromoaniline moiety interacts with Tyr358′ (where ′ denotes a residue from the adjacent subunit; FIG. 71 ).
  • This residue forms a hydrogen bonding network involving Glu329, Ser354, Thr221 and possibly the amide nitrogen of C64 ( FIG. 71 ).
  • Ser22′, Pro26′, Ala165, Gly357′ form the remainder of the inhibitor binding pocket. With the exception of Thr221, all of these residues are different in human IMPDHs ( FIG. 71 ). Thus these interactions account for the selectivity of C64 for CpIMPDH over human IMPDHs.
  • the structure also revealed the presence of a cavity adjacent to the bromoaniline moiety ( FIG. 70 ), which suggested that more potent inhibitors might be created by increasing the bulk of this substituent.
  • Additional benzimidazole based inhibitors were prepared by condensing o-phenylenediamine ( FIG. 55 , 1) with thiazole carboxaldehydes ( FIG. 55 , 2) in the presence of the oxidizing reagent sodium metabisulfite ( FIG. 55 , 3). The resulting 2-substituted benzimidazoles ( FIG. 55 , 4) were then coupled with different bromoacetylamides ( FIG. 55 , 5) under mild basic conditions to give the new analogs ( FIG. 55 , 6).
  • the CpIMPDH inhibitory activity of the compounds was assessed by monitoring the production of NADH by fluorescence ( FIG. 55 ).
  • Replacing the p-MeO of the parent compound C with Cl or Br increased potency by 10-fold (C10, aka 126) and 20-fold (C14, aka 130), respectively, as has been similarly observed with another inhibitor series.
  • the para-substituted aniline group was replaced with 3,4-dichloroaniline (C86) or 2-naphthylamine (C90); the addition of a second Cl improved potency by a factor of 2, while fusing an additional aromatic ring increased potency by a factor of 8.
  • This molecule has demonstrated uncompetitive inhibition with respect to IMP and noncompetitive (mixed) inhibition with respect to NAD + . It was also shown to bind the nicotinamide subsite and to directly or indirectly impose on the ADP site.
  • SAR structure-activity relationship
  • the benzimidazole analogs were synthesized following the procedure outlined in FIG. 55 .
  • Various acetylamide derivatives ( FIG. 55 , 3) were prepared by treating substituted anilines ( FIG. 55 , 1) with bromo acetylchloride ( FIG. 55 , 2) in dichloromethane (DCM) and in the presence of catalytic amounts of N,N-dimethylaminopyridine (DMAP).
  • Various 2-substituted benzimidazoles FIG. 55 , 6) were prepared by condensing O-phenylene diamine ( FIG. 55 , 4) with aromatic aldehydes followed by oxidation in the presence of sodium metabisulfite.
  • 2-substituted benzimidazoles were coupled with the acetylamides ( FIG. 55 , 3) in the presence of potassium carbonate to yield derivatives of C.
  • Cp-IMPDH inhibitory activity for the various prepared compounds was conducted utilizing an assay measuring the conversion of IMP to XMP by monitoring the production of NADH by fluorescence emission in the presence of varying inhibitor concentrations. Chlorine and bromine are found to be more effective substituents at the para-position of the aniline ring ( FIGS. 21-23 ). On the contrary, ortho and meta substitutions were devoid of inhibition activity.
  • Phenyl (C17, compound 133), pyridyl (C16, compound 132) rings are also tolerated in the 2-position.
  • Substituted phenyls (C31 (compound 147), C59 (compound 169)) are not as active as the non-substituted.
  • the potent inhibitor C64 (compound 174) has been co-crystallized with Cp-IMPDH.
  • the co-crystallized structure of Cp-IMPDH with C64 is solved and the SAR matches perfectly well with the structure.
  • 2-aromatic substitution in the benzimidazole portion is important since it interacts with the IMP in the active site according to the crystal structure.
  • the amide bond is also very important for the activity since it could potentially form hydrogen bonding with the active site residues.
  • FIG. 57 summarizes the main differences between the two parasites in this pathway.
  • T. gondii knockout mutant that, like C. parvum , lacks the ability to salvage xanthine and guanine via HXGPRT ( T. gondii - ⁇ HXGPRT (10)) and introduced the CpIMPDH gene under the control of a T. gondii promoter.
  • HXGPRT T. gondii - ⁇ HXGPRT (10)
  • gondii IMPDH gene was disrupted by replacing the entire coding sequence with a chloramphenicol acetyl transferase cassette using a new cosmid-based gene targeting approach. Successful disruption of the gene was confirmed by PCR and Southern blotting; note that numerous attempts by independent laboratories failed to target this locus using smaller plasmid-based constructs. This manipulation created strain T. gondii -CpIMPDH- ⁇ HXGPRT- ⁇ TgIMPDH. Lastly, we introduced a fluorescent protein cassette and isolated stable transgenic parasites by cell sorting. The resulting strain is referred to as T. gondii -CpIMPDH.
  • T. gondii -CpIMPDH a potent inhibitor of eukaryotic IMPDHs including TgIMPDH but a very poor inhibitor of prokaryotic IMPDHs.
  • CpIMDPH is of prokaryotic origin and not inhibited by MPA. As predicted, both wild-type T. gondii and T.
  • gondii -AHXGPRT are sensitive to MPA ( FIG. 57 ), but T. gondii -CpIMPDH is resistant ( FIG. 57 ).
  • Supplementation of the media with xanthine (0.33 mM) essentially renders wild-type T. gondii MPA resistant (EC 50 ⁇ 78 ⁇ M), but has no effect on T. gondii - ⁇ HXGPRT ( FIG.
  • T. gondii model system provides a powerful tool for the evaluation of in vivo efficacy, selectivity, and specificity of CpIMPDH inhibitors.
  • Compounds that selectively inhibit CpIMPDH will block the proliferation of T. gondii -CpIMPDH but not the wild-type and T. gondii -AHXGPRT strains that depend on an enzyme much like the human host.
  • non-specific compounds that have off-target activities in the parasite or the host cell will inhibit the growth of all three strains.
  • a general non-selective inhibitor of both prokaryotic and eukaryotic IMPDH inhibitors will block the proliferation of both T.
  • gondii -CpIMPDH and T. gondii - ⁇ HXGPRT will have no effect on the wild-type strain; note that such compounds should be detected in our enzyme assays and eliminated before they reach this screen.
  • compounds showing poor efficacy against the T. gondii -CpIMPDH parasite may signal problems pertaining to compound uptake, stability or metabolism. Examples of these varied outcomes are discussed below.
  • VVL Fluorescent Vicia villosa lectin
  • Plates are fixed, permeabilized and stained with FITC-VVL and DAPI to numerate parasites and host cells, respectively.
  • FITC-VVL and DAPI to numerate parasites and host cells, respectively.
  • the instrument is programmed to automatically move from well to well, focus and acquire 20 ⁇ M deep image stacks for the entire plate.
  • a series of automated image compression, manipulation, and object-finding algorithms was optimized for the recognition of host cells and parasites using the DAPI and FITC channels.
  • control wells are included for background subtraction.
  • the massive data output is stored, managed and accessed through an Accelrys pipeline database that performs further statistical analyses and transforms raw counts into percentage growth relative to a “no drug” control.
  • the EC 50 for paromomycin as measured with this assay was 97 ⁇ M ( FIG. 58 ), which isin good agreement with several previous studies (reported EC 50 ranges from 65-130 ⁇ M. However, at very high concentrations of paromomycin we only detect ⁇ 70% reduction in parasite number, this may be due to the labelling of sporozoites that invade the host cell monolayer and subsequently die or become arrested in development. Interestingly paromomycin was also found to significantly reduce the mean parasite area in a dose responsive manner ( FIG. 58 ) and might be consistent with the parasites present at high paromomycin concentrations being developmentally arrested.
  • FIG. 58 shows a 2-fold titration of oocysts where the highest inoculum as 1.2 ⁇ 10 6 oocysts per well, for C. parvum growth assays 5 ⁇ 10 5 oocysts were added per well.
  • HCT-8 human ileocecal adenocarcinoma epithelial cell line, HCT-8, which is commonly used to maintain C. parvum infection in tissue culture, was engineered to constitutively express a green fluorescent protein (GFP). Growth of this cell line was monitored daily using a fluorescent plate reader.
  • GFP green fluorescent protein
  • FIG. 59 shows representative data for fourteen 1,2,3-triazole derivatives in the T. gondii model.
  • A99 (22) is ⁇ 17-fold selective and the remaining compounds range in selectivity from 0.9-14-fold ( FIG. 59 ). All compounds have similar effects on both wild-type and T. gondii - ⁇ HXGPRT parasites ( FIG. 59 ), indicating that the lack of selectivity derives from off-target effects unrelated to TgIMPDH.
  • Host cell growth was also assayed to assess the contribution of host cell effects to antiparasitic activity ( FIGS. 59 , 62 , and 64 ).
  • strong host cell effects are observed in compounds that display little selectivity in the T. gondii model ( FIGS. 59 , 62 , and 64 ).
  • compounds that inhibited the proliferation of wild-type T. gondii with EC 50 ⁇ 10 ⁇ M also inhibited the proliferation of host cells.
  • Three compounds (A82, A90, and A105) display little selectivity in the T.
  • gondii model and do not inhibit host cell growth, suggesting that the antiparasitic activities of A82, A90, and A105 do not result from the inhibition of CpIMPDH or TgIMPDH. Instead, A82, A90, and A105 may act on other T. gondii targets not present in the host cell. Conversely, A100, A102, and A103 have EC 50 >20 ⁇ M against wild-type T. gondii yet inhibit HCT-8 cell growth significantly at 12.5 ⁇ M and 25 ⁇ M ( FIG. 62 ).
  • the high-content imaging assay was used to evaluate the anti-cryptosporidial activity of the 1,2,3-triazole CpIMPDH inhibitors at 12.5 ⁇ M and 25 ⁇ M ( FIG. 59 ). All compounds inhibited C. parvum growth by at least 48% at a concentration of 25 ⁇ M ( FIG. 59 ) and thus had equal or markedly improved anticryptosporidial efficacy when compared to parent compound A (53) (EC 50 25 ⁇ M-50 ⁇ M). Unlike paromomycin, a significant reduction in parasite area was not detected (data not shown). The average area of the host cell nucleus was also recorded as a potential indicator of host cell cytotoxicity and likewise no significant change in host cell nuclei size was detected (data not shown). Encouragingly there was a negative trend between anticryptosporidial activity and host cell growth inhibition (data not shown), indicating that improvements in anticryptosporidial activity are not coincident with secondary effects on the host cell.
  • T. gondii -CpIMPDH model provides valuable information regarding compound specificity and is a fast and highly informative filter for compound progression through medicinal chemistry optimization.
  • T. gondii model parasite that mirrors Cryptosporidium purine nucleotide pathways and depends on CpIMPDH.
  • the T. gondii model reliably eliminates compounds from further consideration and provides a useful filter to identify off-target activities.
  • efficacy in the T. gondii model does not always guarantee anti-cryptosporidial activity.
  • T. gondii and C. parvum infect different tissues, and occupy different intracellular compartments.
  • the parasitophorous membrane of T. gondii is in direct contact with the host cell cytoplasm.
  • C. parvum remains beneath the apical membrane of the host cell and is considered ‘extracytoplasmic’ due to the presence of a parasite induced host cell actin patch along with other peculiar and still largely uncharacterized structures including a dense band visible in electron micrographs. This band separates the parasite's parasitophorous vacuole from the host cell cytoplasm and has been hypothesized to be involved in drug and nutrient uptake.
  • the two parasites, and their respective host cells have different repertoires of drug efflux transporters, which can also account for the differences in inhibitor sensitivity.
  • T. gondii assay does not fully negate the necessity of testing in Cryptosporidium directly, it has proven indispensable to winnow candidate compounds to a manageable number amenable to this more challenging model.
  • HCT-8 human ileocecal adenocarcinoma epithelial cell line
  • HCT-8 cells were maintained in RPMI-1640 (Hyclone) supplemented with 10% FBS, 1 mM sodium pyruvate, 50 U/m penicillin, 50 ⁇ g/mL streptomycin, and amphotericin B.
  • Cryptosporidium parvum oocysts were a kind gift from either Dr. Mead (Emory University) of Dr Kissinger (University of Georgia). Purified oocysts were received in 2% potassium dichromate and stored at 4° C. for up to 4 months.
  • HCl assay For the HCl assay the day prior to infection 200 000 HCT-8 cells were seeded into black, optical quality, thin bottom, 96-well plates (DB Falcom) to achieve a 70% confluent monolayer on the day of infection. To facilitate oocyst excystation a procedure described by Gut et al., was followed. Briefly, oocysts were washed twice with 1 mL of PBS (pH7.2), incubated for 10 minutes at 37° C. in 1 mL 10 mM of HCl and then incubated for a further 10 minutes in 0.2 mL of 200 ⁇ M sodium taurocholate at 15° C.
  • PBS pH7.2
  • This oocyst suspension was diluted directly with DMEM (Hyclone) supplemented with 2% FBS, 50 U/m penicillin, 50 ⁇ g/mL streptomycin, amphotericin B and 0.2 mM L-glutamine (infection medium) to inoculate host cell monolayers at 5 ⁇ 10 5 oocysts per well.
  • Oocysts were cultured on host cell monolayers for 3 hours at 37° C.
  • Unexcysted oocysts and oocyst walls were then removed by aspiration and each well washed with 0.2 mL PBS (pH7.2). Infection medium was then added to the monolayers and infection was allowed to progress for 48 hours.
  • VVL IFA was performed in a 96-well format as follows. Following 48 hours of culture C. parvum infected HCT-8 monolayers were washed with 0.2 mL/well PBS and the monolayer was fixed with 0.2 mL/well of 3% paraformaldehyde/PBS, permeabilized with 0.25% Triton-X-100/PBS and blocked with 4% BSA/PBS. When necessary plates were stored at 4° C. for up to 2 weeks 0.1 mL of fluorescein (FITC)-conjugated VVL (Vector Labs) at 0.5 ⁇ g/mL in 1% BSA/PBS was applied to wells and incubated for 45 minutes.
  • FITC fluorescein
  • the plates were washed twice with 200 ⁇ L/well of PBS, in the first wash DAPI at 0.1 ⁇ g/mL was included. Finally 200 ⁇ L/well of PBS was added to the plates prior to storage at 4° C. protected from light.
  • confocal images were acquired using a scanning microscope (BD Biosciences Bioimager P435).
  • the object finding analysis step recorded the number and area of objects per montage image, the output files and a plate map file were then passed onto an automated analysis pipeline (Pipeline Pilot Software, Accelrys) to calculate, the mean number of parasites, the ratio of parasite number to host cell nuclei number, the mean area of parasites and host cell nuclei by well and percentage growth by treatment as compared to the no drug control.
  • These analyses were output in graphical format in one PDF file per plate and the numerical values tabulated in html format.
  • test compounds were stored as 0.1 M stocks in DMSO at ⁇ 20° C. and further diluted in DMSO to a 200 ⁇ working stocks for each dilution, such that the final concentration of DMSO in the infection medium was 0.5%.
  • DMSO DMSO alone was added to triplicate wells.
  • a high paromomycin concentration 0.8 mg/mL was included on each plate in triplicate wells. Plates where this paromomycin control did not inhibit 70-80% of parasite growth were manually inspected to confirm appropriate imaging and analysis. Plates were omitted from final analysis where it was apparent that a lack of inhibition was due to poor parasite growth.
  • HCT-8 cells were transfected with the pmaxGFP plasmid (Amaxa) using Lipofectamine (Invitrogen) following the manufactures instruction. Fluorescent lines were then selected and cloned using FACS. Confluent monolayers of pmaxGFP expressing cells were harvested from T75 flasks and passed through a 40 ⁇ m cell strainer. Cells were then seeded at 4000 cells per well in a volume of 200 ⁇ L into black, optical quality, thin bottom, 96-well plates (DB Falcon). All test compounds were diluted in DMSO to prepare a 200 ⁇ working stock for each dilution. Appropriate wells were spiked with 1 ⁇ l such that the final concentration of DMSO was 0.5%. The fluorescence was read daily with a SpectraMax M22/M2e (Molecular Devices) plate reader (Ex 485, Em 530) for 6-7 days. The percent inhibition was calculated on a day within the exponential phase of growth.
  • CpIMPDH The protozoan parasite Cryptosporidium parvum is a major cause of gastrointestinal disease; no effective drug treatment exists to treat this infection.
  • CpIMPDH is most closely related to prokaryotic IMPDHs, suggesting that the parasite obtained its IMPDH gene via horizontal transfer.
  • inhibitors of CpIMPDH that do not inhibit human IMPDHs.
  • these compounds also inhibit IMPDHs from Helicobacter pylori, Borrelia burgdorferi , and Streptococcus pyogenes , but not IMPDHs from Escherichia coli, Tritrichomonas foetus and Leishmania donovani .
  • a second generation inhibitor blocks H. pylori growth.
  • IMPDH-targeted inhibitors represent a new class of antibiotics for treatment of a wide variety of pathogenic bacteria, including extensively drug resistant strains.
  • the inhibitors of the CpIMPDH might be broad spectrum inhibitors of prokaryotic IMPDHs.
  • IMPDHs from H. pylori the causative agent of gastric ulcer/stomach cancer
  • Borrelia burgdorferi the causative agent of Lyme disease
  • Streptococcus pyogenes a major cause of nosocomial infections
  • a second generation CpIMPDH inhibitor blocks H. pylori growth, demonstrating that these compounds have antibacterial activity.
  • a structural motif is identified that defines susceptible enzymes; this motif is found in a wide variety of pathogenic bacteria.
  • prokaryotic IMPDHs from representative organisms: H. pylori (Gram negative ⁇ proteobacteria), E. coli (Gram negative ⁇ proteobacteria), B. burgdorferi (spirochete), S. pyogenes (Gram positive) and the protozoan parasite T. foetus , which also appears to have obtained its IMPDH gene from a prokaryote.
  • CpIMPDH is most closely related to HpIMPDH ( FIG. 68 ), but also has ⁇ 50% sequence identity to EcIMPDH, BbIMPDH and SpIMPDH.
  • HpIMPDH the enzyme most similar to CpIMPDH.
  • G the enzyme most similar to CpIMPDH.
  • all of the compounds have similar potency for both enzymes, with values of IC 50 ranging from 0.6 to 5 ⁇ M.
  • A-H are noncompetitive (mixed) inhibitors of HpIMPDH with respect to NAD + (data not shown), as observed with CpIMPDH.
  • K i and IC 50 are similar, as expected for noncompetitive inhibition.
  • the compounds also inhibit BbIMPDH with similar potency to CpIMPDH and HpIMPDH ( FIG. 67 ).
  • G and H are submicromolar inhibitors of SpIMPDH
  • A-F are markedly less effective against this enzyme, with IC 50 values ranging from 13 to 90 ⁇ M.
  • No inhibition of EcIMPDH and TfIMPDH is observed at 100 indicating that the values of IC 50 for A-H must be >1000 ⁇ M. This result is especially surprising for EcIMPDH because this enzyme has the same overall similarity to CpIMPDH as the sensitive enzymes.
  • A-H do not inhibit LdIMPDH.
  • H. pylori is cultured in a nutrient rich medium ( Brucella broth), which provides a stringent test for the antibiotic potential of IMPDH-targeted inhibitors.
  • FIG. 69 shows that 20 ⁇ M C91 is sufficient to block the proliferation of a H. pylori culture exiting stationary phase. Higher concentrations of C91 display bacteriocidal effects, with only 23% of the colony forming units remaining after 24 hr treatment with 200 ⁇ M. Exponentially growing H. pylori cells are also sensitive to C91; a concentration of 60 ⁇ M is sufficient to block growth while higher concentrations are bacteriocidal.
  • CpIMPDH with the second generation inhibitor C64 identifies a possible binding site for the inhibitors A-H ( FIGS. 70 and 71 ).
  • IMPDH is a tetramer; surprisingly, C64 binds across a dimer interface, bending around Ala165 and stacking with Tyr358. Both Ala165 and Tyr358 are conserved in the sensitive enzymes, but diverged in the resistant enzymes, suggesting that these residues determine susceptibility to the C series inhibitors, and possibly the other compounds.
  • IMPDH undergoes a conformational change in the middle of its catalytic cycle that brings a mobile flap into the NAD site ( FIG. 68 ).
  • the competition of the flap for this site can be an important determinant of inhibitor susceptibility, and might explain the low susceptibility of SpIMPDH despite the presence of Ala165 and Tyr358 ( FIG. 67 ). Therefore we determined the equilibrium between open and closed conformations (K c ) using a multiple inhibitor experiment.
  • Tiazofurin inhibition illustrates the magnitude of the conformational contribution to inhibitor selectivity.
  • the tiazofurin binding site is conserved among prokaryotic IMPDHs, which predicts that CpIMPDH, HpIMPDH, BbIMPDH, SpIMPDH, EcIMPDH and TfIMPDH should all bind tiazofurin with similar affinity, yet the values of K i vary from 1-69 mM.
  • the resulting “intrinsic values” are indeed nearly identical, ranging from 0.3-0.7 mM.
  • the intrinsic values of K i for ADP range from 0.2-9 mM, reflecting the structural divergence of the ADP binding sites.
  • Ala165 and Tyr358 comprise a structural motif that defines enzymes susceptible to CpIMPDH inhibitors.
  • a BLAST search reveals that these critical residues are present in IMPDHs from a wide variety of pathogenic bacteria in addition to C. parvum, B. burgdorferi and H. pylori: Campylobacter lari (food poisoning), Campylobacter jejuni (food poisoning), Arcobacter butzleri (food poisoning), Bacteroides capillosis (abscesses), Fusobacterium nucleatum (periodontitis, Lemierre's syndrome, skin ulcers), Burkholderia cenocepacia (infection in Cystic Fibrosis), S.
  • Inosine 5′-monophosphate dehydrogenase IMPDH
  • IMPDH Inosine 5′-monophosphate dehydrogenase
  • Cryptosporidium parvum a major cause of diarrhea and malnutrition and a potential bioterrorism agent.
  • CpIMPDH is most closely related to prokaryotic IMPDHs, suggesting that the parasite obtained its IMPDH gene via horizontal transfer.
  • T. foetus, B. burgdorferi, E. coli and C. parvum IMPDH were expressed in guaB strains of E. coli (which lack endogenous IMPDH) and purified as described previously.
  • the S250A, L444Y and S250A/L444Y mutants of E. coli IMPDH were constructed using Quikchange (Stratagene, La Jolla, Calif.). Enzymes were expressed and purified as previously described.
  • a NcoI site was created at the beginning of the LdIMPDH coding sequence and the NcoI-PstI fragment was cloned into pKK233-2 to create the plasmid pLDI, which expresses LdIMPDH under control of the trc promoter.
  • Cultures were induced with 0.5 mM IPTG and grown overnight. Cells were harvested by centrifugation, resuspended in Buffer A, lysed by sonication and clarified by centrifugation followed by filtration through a 45 ⁇ m cellulose acetate filter.
  • Protein was applied to a Poros HS strong cation exchange resin (PerSeptive Biosystems) pre-equilibrated with 20 mM NaP i , pH 7.5, 1 mM DTT (Buffer B). LdIMPDH was eluted with a gradient of 0-0.9 M NaCl. Fractions containing IMPDH activity were pooled and applied to IMP affinity resin. The column was washed with Buffer B and enzyme was eluted with Buffer B containing 0.5 M KCl, 1 mM IMP. The specific activity of the final preparation was 2.6 ⁇ moles/min-mg.
  • H. pylori and S. pyogenes guaB genes were cloned into pET28a with 6 ⁇ His-tags.
  • Bacteria were grown at 30° C. in LB medium containing 25 ⁇ g/mL kanamycin until the OD 600 reached approximately 0.6. Expression was initiated by the addition of 0.5 mM IPTG and the temperature was changed to 25° C. Bacteria were harvested after 16 hours. The cell pellet was rinsed (3 ⁇ ) with 50 mM phosphate buffer, 500 mM NaCl, 5 mM imidazole, pH 8.0, 1 mM IMP and 5 mM ⁇ -mercaptoethanol, and lysed by sonication.
  • the lysate was clarified by centrifugation and loaded on a Ni-NTA column (Qiagen).
  • the purified protein were eluted in 50 mM phosphate buffer, 500 mM NaCl, 250 mM imidazole, pH 8.0, 1 mM IMP and 5 mM ⁇ -mercaptoethanol, concentrated and dialyzed against 50 mM Tris-HCl, pH 8.0, and 10% glycerol.
  • the protein concentration was determined by using Bradford dye procedure (BioRad).
  • Enzyme was incubated with inhibitor (50 pM-100 ⁇ M) for 10 min at room temperature prior to addition of substrates.

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WO2010108187A3 (fr) 2011-03-31
EP2408753A4 (fr) 2012-11-07
US20150099781A1 (en) 2015-04-09
US20120101096A1 (en) 2012-04-26

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